ICBDSR Report 2024

Iran TRoCA, 2015 to 2019

total births in the 5-year period: 37,552 (livebirths: 37,009)
average births per year: 7,510 (livebirths: 7,400)
terminations of pregnancy legal in country: Yes
data include terminations of pregnancy: Yes
source structure: Hospital based

A word from the program

The TROCA program is hospital-based, and covers births and children in three university hospitals in the city of Tabriz, in the North-West of Iran. Tabriz is one of the three major cities in the country. The program covers approximately 60-70% of all births (15,000 births per year) in the area, including stillbirths occurring in hospitals and terminations of pregnancy.

Selected data highlights

The following tables highlight selected sets of congenital anomalies, each with a specific focus.

Top Ten

Here are the program’s top ten conditions by frequency, selected among those with significant clinical and public health impact. These are the conditions that one is more likely to encounter in the population under surveillance and impact the largest number of individuals and their families.

Condition	Cases	Yearly Avg	Prevalence
Top 10 Conditions by Frequency
among specific diagnoses with major health impact, Iran TRoCA, 2015-2019 shown are total cases for the reporting period, yearly average cases, and prevalence per 10,000
Down syndrome	52	10	13.8
Hydrocephaly	49	10	13.0
Polydactyly preaxial	41	8	10.9
Cleft lip with or without cleft palate	34	7	9.1
Diaphragmatic hernia	33	7	8.8
Esophageal atresia	32	6	8.5
Spina bifida	29	6	7.7
Transposition of great vessels	26	5	6.9
Hypoplastic left heart syndrome	25	5	6.7
Anorectal atresia/stenosis	24	5	6.4

Notable Seven

These conditions exemplify the impact of congenital anomalies on morbidity and mortality. For example, neural tube defects and critical congenital heart disease, when combined, account for approximately half of all infant deaths associated with congenital anomalies.

For several of these conditions, modifiable risk factors are well established, and primary prevention, if implemented appropriately, works. This implication is unpacked in a later section (‘what if scenario’).

	Yearly cases		Percent liveborn	Prevalence per 10,000
Seven highly impactful conditions
selected on the basis of high morbidity and mortality, and potential for primary prevention Iran TRoCA, 2015-2019
	Program	Country	Percent liveborn	Prevalence per 10,000
Neural tube defects (NTD)
Neural tube defects, total	7	1161	95	9.9
Spina bifida	6	903	97	7.7
Anencephaly	1	152	80	1.3
Orofacial
Cleft lip with or without cleft palate	7	1067	88	9.1
Cleft palate without cleft lip	4	598	100	5.1
Heart
Transposition of great vessels	5	809	100	6.9
Hypoplastic left heart syndrome	5	786	92	6.7
Tetralogy of Fallot	3	504	94	4.3
Estimated from program prevalence extrapolated to total country births. Iran births for 2022 from World Bank

The full table

This more expansive set of major congenital anomalies, internal and external, includes most conditions of significant clinical and public health impact. A more detailed view of Trisomy 21 (Down syndrome) is included in a later section. Note: a child with multiple anomalies will be counted in all pertinent rows.

	All births			Livebirths
Selected congenital conditions by system
number of cases and prevalence (prev) per 10,000, for all births and livebirths Iran TRoCA, 2015-2019
	Cases	Prev	95% CI	Cases	Prev	95% CI
Neural tube defects (NTD)
Neural tube defects, total	37	9.9	6.9 - 13.6	35	9.5	6.3 - 12.6
Spina bifida	29	7.7	5.2 - 11.1	28	7.6	4.8 - 10.4
Anencephaly	5	1.3	0.4 - 3.1	4	1.1	0.3 - 2.8
Encephalocele	3	0.8	0.2 - 2.3	3	0.8	0.2 - 2.4
Other brain
Hydrocephaly	49	13.0	9.7 - 17.3	46	12.4	8.8 - 16.0
Microcephaly	24	6.4	4.1 - 9.5	23	6.2	3.7 - 8.8
Holoprosencephaly	2	0.5	0.1 - 1.9	1	0.3	0.0 - 1.5
Eye and Ear
A/microtia, unspec.	60	16.0	12.2 - 20.6	59	15.9	11.9 - 20.0
A/microphthalmia, unspec.	6	1.6	0.6 - 3.5	6	1.6	0.3 - 2.9
Microphthalmos	3	0.8	0.2 - 2.3	3	0.8	0.2 - 2.4
Anophthalmos	0	0.0	0.0 - 1.0	0	0.0	0.0 - 1.0
Anotia	0	0.0	0.0 - 1.0	0	0.0	0.0 - 1.0
Microtia	0	0.0	0.0 - 1.0	0	0.0	0.0 - 1.0
Orofacial
Cleft lip with or without cleft palate	34	9.1	6.3 - 12.7	30	8.1	5.2 - 11.0
Cleft palate without cleft lip	19	5.1	3.0 - 7.9	19	5.1	2.8 - 7.4
Choanal atresia bilateral	10	2.7	1.3 - 4.9	10	2.7	1.0 - 4.4
Heart
Transposition of great vessels	26	6.9	4.5 - 10.1	26	7.0	4.3 - 9.7
Hypoplastic left heart syndrome	25	6.7	4.3 - 9.8	23	6.2	3.7 - 8.8
Tetralogy of Fallot	16	4.3	2.4 - 6.9	15	4.1	2.0 - 6.1
Coarctation of aorta	9	2.4	1.1 - 4.5	9	2.4	0.8 - 4.0
Gastrointestinal
Esophageal atresia	32	8.5	5.8 - 12.0	31	8.4	5.4 - 11.3
Anorectal atresia/stenosis	24	6.4	4.1 - 9.5	22	5.9	3.5 - 8.4
Small intestinal atresia/stenosis	16	4.3	2.4 - 6.9	16	4.3	2.2 - 6.4
Genitourinary
Undescended testis	320	85.2	76.1 - 95.1	306	82.7	73.5 - 91.9
Hypospadias	154	41.0	34.8 - 48.0	149	40.3	33.8 - 46.7
Renal agenesis	8	2.1	0.9 - 4.2	7	1.9	0.5 - 3.3
Cystic kidney	5	1.3	0.4 - 3.1	2	0.5	0.1 - 2.0
Bladder exstrophy	1	0.3	0.0 - 1.5	1	0.3	0.0 - 1.5
Epispadias	0	0.0	0.0 - 1.0	0	0.0	0.0 - 1.0
Indeterminate sex	0	0.0	0.0 - 1.0	0	0.0	0.0 - 1.0
Limb
Limb deficiency (LD), total	62	16.5	12.7 - 21.2	62	16.8	12.6 - 20.9
Polydactyly preaxial	41	10.9	7.8 - 14.8	41	11.1	7.7 - 14.5
LD unspec.	9	2.4	1.1 - 4.5	9	2.4	0.8 - 4.0
LD transverse	0	0.0	0.0 - 1.0	0	0.0	0.0 - 1.0
LD preaxial	0	0.0	0.0 - 1.0	0	0.0	0.0 - 1.0
LD postaxial	0	0.0	0.0 - 1.0	0	0.0	0.0 - 1.0
LD axial	0	0.0	0.0 - 1.0	0	0.0	0.0 - 1.0
LD intercalary	0	0.0	0.0 - 1.0	0	0.0	0.0 - 1.0
LD mixed	0	0.0	0.0 - 1.0	0	0.0	0.0 - 1.0
Abdominal
Diaphragmatic hernia	33	8.8	6.0 - 12.3	32	8.6	5.7 - 11.6
Omphalocele	23	6.1	3.9 - 9.2	22	5.9	3.5 - 8.4
Omphalocele/Gastroschisis, unspec.	7	1.9	0.7 - 3.8	6	1.6	0.3 - 2.9
Gastroschisis	2	0.5	0.1 - 1.9	0	0.0	0.0 - 1.0
Prune belly sequence	0	0.0	0.0 - 1.0	0	0.0	0.0 - 1.0
Chromosomal
Down syndrome	52	13.8	10.3 - 18.2	43	11.6	8.1 - 15.1
Trisomy 18	2	0.5	0.1 - 1.9	2	0.5	0.1 - 2.0
Trisomy 13	1	0.3	0.0 - 1.5	1	0.3	0.0 - 1.5
Note a dash (-) indicates data not available or not provided

Program Comment

The program leads provide their insights on data, operations, and recent achievements. Their interpretation of the data is particularly valuable because of their local experience and knowledge.

Total prevalence of anomalies has more than tripled in the region over the past two decades. Early records show that nervous system and genitourinary tract anomalies were the most frequent defects, while later data indicated that heart and limb defects are the most common ones.
There was an unusual increase occurred for the total prevalence of congenital anomalies in 2002 in the registry region. TRoCA, broadly, recorded a low rate for spina bifida, high rates for anencephaly, hydrocephaly, and cleft palate without cleft lip, and limb reduction defects in the region. We do not know for sure whether any change in these rates is due to a true existence/absence of epidemics in the region, due to the technical failure of our monitoring, or due to etiologic and environmental teratogens. The reasons behind the high/low rates of some groups of anomalies are still unclear.

Down syndrome (trisomy 21)

By far the most common chromosomal anomaly, Down syndrome is known to occur more frequently (has a higher risk of occurrence) in births of women with higher maternal age

This pattern is universally observed, provided there is no significant bias toward missing pregnancies with Down syndrome in older women (e.g., because of unreported pregnancy terminations)

	All cases			Livebirths
Down syndrome, overall and by maternal age
separately for all births and livebirths, prevalence per 10,000 (Poisson exact confidence intervals) Iran TRoCA, 2015-2019
	Cases	Prev	95% CI	Cases	Prev	95% CI
All maternal ages	52	13.8	10.3 - 18.2	43	11.6	8.1 - 15.1
< 20 years	2	4.9	0.6 - 17.7	2	4.9	0.6 - 17.7
20 to 24	7	8.0	3.2 - 16.5	6	6.9	1.4 - 12.4
25 to 29	4	3.8	1.0 - 9.8	3	2.9	0.6 - 8.4
30 to 34	14	17.0	9.3 - 28.5	14	17.0	8.1 - 25.9
35 to 39	13	28.9	15.4 - 49.5	9	20.0	7.0 - 33.1
40 to 44	12	94.5	48.8 - 165.1	9	70.9	24.7 - 117.0
45+ years	0	0.0	0.0 - 217.2	0	0.0	0.0 - 217.2
Age unspec.	0	-	-	0	-	-
Age unspec. = maternal age unknown or unspecified

Down syndrome - maternal age pyramid

Because of the relation between prevalence of Down syndrome and maternal age, the maternal age distribution in the population is a major determinant of the number of conceptions with Down syndrome in the population.

For programs that have maternal age specific data, one can compare the maternal-age ‘pyramid’ for all births in the population with that of births with Down syndrome. Typically, the distribution is skewed, with a relative excess of births with Down syndrome among the more advanced maternal age groups.

Down syndrome - birth rates matter

Despite the considerably higher risk (rates) of Down syndrome in mothers over 40 or 45 years, these age groups contribute comparatively fewer affected births than younger age groups. This is because birth rates matter: fewer births in the more advanced age groups mean fewer cases overall from those age groups.

A Pareto chart helps highlight the cumulative contribution of different age groups to the total number of cases. This information can help inform strategies for testing and counseling.

Linking risk factor profile and congenital anomalies

The term triple surveillance refers to a model of public health surveillance that births includes the full causal chain, from a) risk factors, which influence the number of affected pregnancies; to b) the affected pregnancies themselves, that are vulnerable to adverse health outcomes; and to c) the health outcomes in affected individuals. The burden of risk becomes expressed eventually in the burden of disease.

Historically, birth defect surveillance has focused on the second element, the occurrence of congenital anomalies.

However, improving outcomes (morbidity, mortality, disability) requires understanding and tracking risk factors (to improve primary prevention) and health outcomes (to improve care). Triple surveillance advocates integrating the tracking of all three elements in this causal chain. Together, these three domains provide clinicians, public health professionals, and policy makers with information to act.

To highlight such context, the next sections provide elements of country demographics, outcomes (mainly early mortality), and selected risk factors. These data, particularly those on risk factors and outcomes, are sometimes directly measured, and sometimes estimated. Birth defect programs with their partners can supplement these data with local assessments.

Country demographics

A surveillance program operates within its country’s demographic situation and trends. This information adds meaning and context to birth defect surveillance information.

Key Indicator	2022 data
Demographic Indicators, Iran
on population, births, life expectancy
Total population	88,550,570
Number of births	1,172,587
Birth rate (per 1000 pop)	13.2
Fertility (births per woman)	1.7
Life expectancy at birth (years)	74.6
Source: World Bank (accessed Sept 2024)

From program to country

Many (though not all) programs cover a proportion of the country in which they operate. In this setting, a common question is what the program can tell use about the impact of congenital anomalies country-wide, under the assumption that the program information is a good estimator for the country itself. This assumption, of course, needs to be carefully examined, and the program staff typically has the local knowledge to help frame such estimates within the strengths and limitations of the data.

The table below uses the prevalence measured within the program to estimate the number of births with selected congenital anomalies for the entire country. These extrapolations have limitations, and in most cases are illustrative. However, at times a program that covers a proportion of the population may be the only practical window into congenital anomalies country-wide.

	All cases	liveborn
A window into the country: Iran, 2022 estimates
Country-wide estimates for selected conditions (1,172,587 births), extrapolating from program data
Neural tube defects (NTD)
Neural tube defects, total	1155	1109
Spina bifida	906	887
Anencephaly	156	127
Encephalocele	94	95
Other brain
Hydrocephaly	1530	1457
Microcephaly	749	729
Holoprosencephaly	62	32
Eye and Ear
A/microtia, unspec.	1874	1869
A/microphthalmia, unspec.	187	190
Microphthalmos	94	95
Orofacial
Cleft lip with or without cleft palate	1062	951
Cleft palate without cleft lip	593	602
Choanal atresia bilateral	312	317
Heart
Transposition of great vessels	812	824
Hypoplastic left heart syndrome	781	729
Tetralogy of Fallot	500	475
Coarctation of aorta	281	285
Gastrointestinal
Esophageal atresia	999	982
Anorectal atresia/stenosis	749	697
Small intestinal atresia/stenosis	500	507
Genitourinary
Undescended testis	9992	9695
Hypospadias	4809	4721
Renal agenesis	250	222
Cystic kidney	156	63
Bladder exstrophy	31	32
Limb
Limb deficiency (LD), total	1936	1964
Polydactyly preaxial	1280	1299
LD unspec.	281	285
Abdominal
Diaphragmatic hernia	1030	1014
Omphalocele	718	697
Omphalocele/Gastroschisis, unspec.	219	190
Gastroschisis	62	0
Chromosomal
Down syndrome	1624	1362
Trisomy 18	62	63
Trisomy 13	31	32
Note: includes conditions with at least 5 estimated cases. Assumes that prevalence estimates from program are valid country-wide.

Outcomes - early mortality

The relative impact of congenital anomalies on early mortality (neonatal, infant, and under 5 years) tends to increase as infant mortality due to other causes falls. This pattern has been observed worldwide. These general indicators of early mortality are tracked regularly by public health agencies.

Key Indicator	2022 data
Mortality Indicators, Iran
Neonatal mortality (per 1000)	7.6
Infant mortality (per 1000)	10.3
Under 5 mortality (per 1000)	12.0
Source: World Bank, accessed Sept 2024

Outcomes - mortality with congenital anomalies

A more specific indicator (infant deaths due to congenital anomalies) is more challenging to document accurately. Missed diagnoses, especially of internal anomalies, can lead to massive underestimates, especially in settings where diagnoses rely only or mostly on an external exam. The table below summarizes data and estimates from systematic public sources. However, local assessments from birth defect surveillance program can help improve the quality of this key indicator.

Age group	Percent	Deaths / 100k pop
Deaths due to birth defects, Iran
among infants (< 1 year old) and from first to fifth birthday
Infants	21.5	253.3
1 to < 5 yrs	15.0	9.7
Source: WHO mortality data 2017 \| who.int

Risk factors

Some modifiable exposures are well-established risk factors for congenital anomalies. Reducing these exposures is the basis for effective primary prevention. Here we focus specifically on smoking, diabetes, and folate insufficiency. These factors, both common and modifiable, increase the risk of major contributors to morbidity and mortality, including orofacial clefts, neural tube defects, and serious congenital heart disease. The impact of these risk factors depend on their frequency in the population. The following tables show frequency estimates for the country. In another section, these data are used to estimate the number of cases in the country potentially preventable by eliminating the risk factors.

Smoking

Smoking is associated with increased risk for many adverse pregnancy outcomes and several congenital anomalies, including orofacial clefts and probably congenital heart disease. The increased risk is relatively modest (odds ratios tipically less than 1.5) but the effect size, or number of cases due to smoking, depends on the rate of smoking among women who become pregnant. Here we used country-specific estimates of smoking in women of reproductive age (see table for references). Rates of smoking during pregnancy tend to be lower, but by the time many women know they are pregnant, the at-risk period for congenital anomalies has often already passed.

Women	Frequency (%)
Smoking in women
Frequency in two different groups, Iran
Of reproductive age	5.9 ( 4.2 - 7.9 )
During pregnancy	NA ( NA - NA )
Source: IHME \| www.healthdata.org \| and Lange 2018

Diabetes

Maternal pregestational diabetes is associated with increased risk for many serious congenital anomalies, including spina bifida, several critical congenital heart defects, and multiple congenital anomalies, among others. In some cases the relative risk (or odds ratio) can be quite high, above 4 or 5 in some cases. The effect size (number of cases due to diabetes) depends on the frequency of diabetes, which tipically increases with age.

Age Group	Percent
Diabetes in women
Frequency by age group, Iran
15 to 19	1.0
20 to 24	1.8
25 to 29	2.7
30 to 34	4.1
35 to 39	6.0
40 to 44	8.6
45 to 49	11.6
Source: IHME \| www.healthdata.org

Folate insufficiency

Folate insufficiency is associated with increased risk for neural tube defects and perhaps other congenital anomalies. On a population-basis, well-implemented folic acid fortification is estimated to decrease the prevalence of neural tube defects below 6 per 10,000 or perhaps even lower. Folic acid fortification is most effective when it is mandatory and universal, meaning that it involves foods commonly consumed by large parts of the population (e.g., wheat, maize, rice, depending on culture and geography).

Mandatory	Food vehicle	Year started
Folic acid fortification
Status of mandatory fortification in Iran
No	-	-
Source: FFI \| fortificationdata.org

What if - prevention scenarios

What follows is a tricky but important exercise. By combining information about risk factors and prevalence of congenital anomalies, one can attempt to estimate the number of cases attributable to risk factors. This is illustrated in the table below, which uses prevalence information from the program and risk factor information (e.g., diabetes frequency in women) from country data. These estimates also require knowing the relative risk of disease given the exposure. Here we use odds ratios derived from high quality studies and metanalyses. These data then are fed into the Levine estimator of attributable fraction to generate the scenarios that you see in the table.

	Prevalence per 10,000	attributable cases			Risk factor parameters
Attributable cases for selected risk factors
yearly estimates in program and in country, and per million births Iran TRoCA, 2015-2019
	Prevalence per 10,000	Program	Country	per 1M births	Risk factor parameters
Neural tube defects (NTD)
Neural tube defects, total	9.9	3	457	390	Presumed folate insufficiency, prevalence > 6
Orofacial
Cleft lip with or without cleft palate	9.1	0	21	18	smoking, freq: 5.9%, OR: 1.34
Cleft palate without cleft lip	5.1	0	8	7	smoking, freq: 5.9%, OR: 1.22
Heart
Transposition of great vessels	6.9	0	48	41	diabetes, freq: 2.7%, OR: 3.34
Hypoplastic left heart syndrome	6.7	0	69	59	diabetes, freq: 2.7%, OR: 4.58
Tetralogy of Fallot	4.3	0	48	41	diabetes, freq: 2.7%, OR: 4.89
Odds ratios from literature, exposure frequencies from country estimates (see methods for details). NTD estimates only when reported prevalence is greater than 6 per 10,000, and where ETOPFA are included or not legally allowed.

Arguably, these estimates are simplistic. For one, they assume accurate inputs. For neural tube defects, the assumption is that the reported prevalence is accurate (e.g., that it includes stillbirths and pregnancy terminations).

On the exposure side, e.g., for smoking and diabetes, they assume that the reported smoking rates in women reflect the smoking rates in the at-risk period, typically the periconceptional period. Smoking rates in pregnancy are typically lower than those among women of childbearing age in general, but many women realize they are pregnant after the at-risk period for many congenital anomalies.

Moreover, these estimates consider risk factors ‘one at the the time’ and do not account, for example, for multiple exposures (e.g., diabetes and smoking) or interactions among multiple exposures. And so on.

Nevertheless, even rough estimates provide an important message. Some instances, perhaps many, of major and even lethal congenital anomalies are preventable by reducing the burden of risk in populations and individuals. Moreover, for many risk factors (smoking and diabetes in particular), the benefits of exposure mitigation extend beyond the prevention of congenital anomalies to the prevention of many other health conditions, for the fetus as well as for parents.